Efeitos da friedelina sobre timócitos e linfócitos e sua influência sobre as células T reguladoras na resposta inflamatória induzida por ovalbumina na asma alérgica experimental

Abstract

Allergic asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness and abnormal airway remodeling. In this disease, the pathogenesis is driven by an intense type 2 immune response and a diminished population of regulatory T cells (Tregs). Currently, inhaled glucocorticoids are the firstline therapy for asthma. However, the prolonged use of these drugs at high doses can cause side effects and increase the risk of other pathologies. Thus, the search for alternatives for asthma treatment is very important. Friedelin, a natural pentacyclic triterpene, has garnered considerable attention due to its wide range of pharmacological actions, including antitumor, anti-inflammatory, analgesic, antipyretic, and antioxidant effects. Despite all these effects, the actions of friedelin on thymocytes and T lymphocytes, as well as its possible anti-inflammatory mechanism of action in experimental allergic asthma have not been explored yet. In this study, we aim to evaluate the effects of friedelin on thymocytes and lymphocytes in vitro and in vivo, as well as to investigate the possible anti-inflammatory mechanism of this triterpene in an experimental model of ovalbumin-induced allergic asthma. Firstly, we confirmed that friedelin did not alter the cell viability of thymocytes at all tested concentrations (0.1 - 100 µM). Then, we observed in vitro that friedelin increased the CXCL12-induced migration in immature thymocytes (CD4-CD8- and CD4+CD8+ ), while inhibiting the migration of CD4+ thymocytes. Additionally, friedelin also reduced the production of the cytokine IL-2 in thymocytes stimulated with concanavalin-A (Con-A). In the population of lymphocytes obtained from axillary lymph nodes, friedelin did not interfere with the migratory response induced by CXCL12 but suppressed the ConA-stimulated IL-2 production. The intraperitoneal injection of friedelin in C57BL6 mice for 4 consecutive days did not induce any noticeable changes in the macroscopic aspects of the thymus, nor did it affect its relative weight. Furthermore, the different thymocyte subsets remained unchanged after treatment with friedelin. On the other hand, treatment with dexamethasone, a reference drug, caused thymic atrophy with marked reduction in the number of thymocytes and thymus weight. Based on the direct effects of friedelin on immune cells, as well as the absence of detrimental effects on the thymus, we decided to evaluate the effects of topical treatment with friedelin in asthma. Our results revealed that friedelin significantly reduced the accumulation of total leukocytes in the airways of OVA-stimulated asthmatic animals. Moreover, friedelin treatment increased the percentage of regulatory T cells in the airways of asthmatic animals, which may justify the anti-inflammatory effects of friedelin. Taken together, these findings indicates that friedelin may be a promising candidate for the treatment of allergic asthma.